Effets des acides gras polyinsaturés n-3 sur les processus cibles des rétinoïdes impliqués dans la plasticité synaptique et la mémoire au cours du vieillissement

Les acides gras polyinsaturés à longue chaîne (AGPI-LC) de la série n-3 jouent un rôle essentiel dans le fonctionnement cérébral, notamment dans le maintien des processus de plasticité synaptique et de mémoire au cours du vieillissement. Il est maintenant bien admis que ces acides gras peuvent moduler la transcription de gènes impliqués dans les processus de plasticité synaptique sous-tendant les performances mnésiques via leur liaison à des récepteurs nucléaires tels que les PPAR (peroxisome proliferator-activated receptor) et les RXR (retinoid X receptor). Les RXR sont les partenaires communs d hétérodimérisation de nombreux autres récepteurs, dont le récepteur nucléaire de l acide rétinoïque (AR), RAR (retinoic acid receptor), métabolite actif de la vitamine A. Ainsi, les RXR jouent un rôle majeur dans la régulation des voies de signalisation des AGPI n-3 et des rétinoïdes.Dans ce contexte, l objectif de notre travail était de mieux comprendre les mécanismes mis en jeu dans l action des AGPI-LC n-3 sur les processus neurobiologiques qui sous-tendent les performances mnésiques au cours du vieillissement, notamment en abordant de manière spécifique les mécanismes mis en jeu dans les interactions entre les voies de signalisation des AGPI-LC n-3 et des rétinoïdes. Les approches expérimentales mises en place ont consisté notamment à évaluer chez le rat âgé les effets de supplémentations nutritionnelles en AGPI-LC n-3 et/ou vitamine A sur les performances de mémoire, ainsi que l action du DHA administré seul sur différents types de mémoire dépendants de l hippocampe.Nos principaux résultats montrent une altération du métabolisme des acides gras et de la vitamine A au cours du vieillissement. Ces changements métaboliques sont associés à une hypoexpression des voies de signalisation des AGPI n-3 et des rétinoïdes, accompagnée de déficits mnésiques. Nous montrons par ailleurs un effet synergique d une supplémentation nutritionnelle en AGPI-LC n-3 et en vitamine A sur le maintien des performances de mémoire chez l animal âgé. De plus, cette supplémentation permet de prévenir, dans l hippocampe, les changements de composition en AGPI n-3 ainsi que l hypoexpression des ARNm de RXRg et de kinases régulées par l AR et les AGPI n-3.Ces résultats plaident en faveur d une action synergique des AGPI-LC n-3 et de la vitamine A sur le maintien des performances mnésiques au cours du vieillissement, via une action combinée sur leurs voies de signalisation, lesquelles participeraient ainsi au maintien de certains processus de plasticité synaptique sous-tendant la mémoire et qui se trouvent être altérés avec l âge.N-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) play a critical role in brain functioning, notably in the maintenance of synaptic plasticity and memory processes during aging. It is now well accepted that n-3 PUFAs can modulate transcription of genes involved in synaptic plasticity processes underlying the memory performances through binding and activating nuclear receptors such as PPARs (peroxisome proliferator-activated receptors), and RXRs (retinoid X receptors). RXRs are the common heterodimerization partner of numerous nuclear receptors, among them the retinoic acid receptor (RAR), which binds retinoic acid (RA), the active metabolite of vitamin A. Thus, RXRs play a key role in the regulation of n-3 PUFA and retinoid signaling pathways.In this context, the aim of this work was to study the mechanisms involved in the action of n-3 PUFAs on neurobiological processes underlying the memory performances during aging, and more particularly by assessing specifically the molecular mechanisms involved in interactions between n-3 PUFA and retinoid signaling pathways. For this purpose, we studied the effects of dietary supplementations in n-3 PUFAs and/or vitamin A on memory performances in aged rats. We also studied the specific effect of unesterified DHA pharmacological treatments on different hippocampal-dependent memory tasks.Our main results showed impairments in fatty acid and vitamin A metabolism during aging. These modifications were associated with an hypoexpression of n-3 PUFA and retinoid signaling pathways, and memory deficits. Furthermore, we demonstrated a synergetic effect of the joint n-3 LC-PUFA and vitamin A dietary supplementation on the maintenance of memory performances in aged rats. Moreover, in the hippocampus, this supplementation prevented the n-3 PUFA compositional changes, and also the mRNA hypoexpression of RXRg and of several kinases regulated by RA and n-3 PUFAs which were observed during aging.These results suggest a beneficial synergetic effect of n-3 LC-PUFAs and vitamin A on the maintenance of memory performances during aging, through a combined action on their signaling pathways, which could be involved in the maintenance of synaptic plasticity processes underlying memory performances impaired during aging.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF

Role of Retinoid X Receptors (RXRs) and dietary vitamin A in Alzheimer's disease: Evidence from clinicopathological and preclinical studies.

BACKGROUND Vitamin A (VitA), via its active metabolite retinoic acid (RA), is critical for the maintenance of memory function with advancing age. Although its role in Alzheimer's disease (AD) is not well understood, data suggest that impaired brain VitA signaling is associated with the accumulation of β-amyloid peptides (Aβ), and could thus contribute to the onset of AD. METHODS We evaluated the protective action of a six-month-long dietary VitA-supplementation (20 IU/g), starting at 8 months of age, on the memory and the neuropathology of the 3xTg-AD mouse model of AD (n = 11-14/group; including 4-6 females and 7-8 males). We also measured protein levels of Retinoic Acid Receptor β (RARβ) and Retinoid X Receptor γ (RXRγ) in homogenates from the inferior parietal cortex of 60 participants of the Religious Orders study (ROS) divided in three groups: no cognitive impairment (NCI) (n = 20), mild cognitive impairment (MCI) (n = 20) and AD (n = 20). RESULTS The VitA-enriched diet preserved spatial memory of 3xTg-AD mice in the Y maze. VitA-supplementation affected hippocampal RXR expression in an opposite way according to sex by tending to increase in males and decrease in females their mRNA expression. VitA-enriched diet also reduced the amount of hippocampal Aβ40 and Aβ42, as well as the phosphorylation of tau protein at sites Ser396/Ser404 (PHF-1) in males. VitA-supplementation had no effect on tau phosphorylation in females but worsened their hippocampal Aβ load. However, the expression of Rxr-β in the hippocampus was negatively correlated with the amount of both soluble and insoluble Aβ in both males and females. Western immunoblotting in the human cortical samples of the ROS study did not reveal differences in RARβ levels. However, it evidenced a switch from a 60-kDa-RXRγ to a 55-kDa-RXRγ in AD, correlating with ante mortem cognitive decline and the accumulation of neuritic plaques in the brain cortex. CONCLUSION Our data suggest that (i) an altered expression of RXRs receptors is a contributor to β-amyloid pathology in both humans and 3xTg-AD mice, (ii) a chronic exposure of 3xTg-AD mice to a VitA-enriched diet may be protective in males, but not in females

Retinoic Acid Restores Adult Hippocampal Neurogenesis and Reverses Spatial Memory Deficit in Vitamin A Deprived Rats

A dysfunction of retinoid hippocampal signaling pathway has been involved in the appearance of affective and cognitive disorders. However, the underlying neurobiological mechanisms remain unknown. Hippocampal granule neurons are generated throughout life and are involved in emotion and memory. Here, we investigated the effects of vitamin A deficiency (VAD) on neurogenesis and memory and the ability of retinoic acid (RA) treatment to prevent VAD-induced impairments. Adult retinoid-deficient rats were generated by a vitamin A-free diet from weaning in order to allow a normal development. The effects of VAD and/or RA administration were examined on hippocampal neurogenesis, retinoid target genes such as neurotrophin receptors and spatial reference memory measured in the water maze. Long-term VAD decreased neurogenesis and led to memory deficits. More importantly, these effects were reversed by 4 weeks of RA treatment. These beneficial effects may be in part related to an up-regulation of retinoid-mediated molecular events, such as the expression of the neurotrophin receptor TrkA. We have demonstrated for the first time that the effect of vitamin A deficient diet on the level of hippoccampal neurogenesis is reversible and that RA treatment is important for the maintenance of the hippocampal plasticity and function

Dietary polyphenol supplementation prevents alterations of spatial navigation in middle-aged mice

Spatial learning and memory deficits associated with hippocampal synaptic plasticity impairments are commonly observed during aging. Besides, the beneficial role of dietary polyphenols has been suggested as potential functional food candidates to prevent this memory decline. Indeed, polyphenols could potentiate the signaling pathways of synaptic plasticity underlying learning and memory. In this study, spatial learning deficits of middle-aged mice were first highlighted and characterized according to their navigation patterns in the Morris water maze task. An eight-week polyphenol-enriched diet, containing a polyphenol-rich extract from grape and blueberry (PEGB; from the Neurophenols Consortium) with high contents of flavonoids, stilbenes and phenolic acids, was then successful in reversing these age-induced effects. The use of spatial strategies was indeed delayed with aging whereas a polyphenol supplementation could promote the occurrence of spatial strategies. These behavioral results were associated with neurobiological changes: while the expression of hippocampal calmodulin kinase II (CaMKII) mRNA levels was reduced in middle-aged animals, the polyphenol-enriched diet could rescue them. Besides, an increased expression of nerve growth neurotrophic factor (NGF) mRNA levels was also observed in supplemented adult and middle-aged mice. Thus these data suggest that supplementation with polyphenols could be an efficient nutritional way to prevent age-induced cognitive decline

Aging decreases the abundance of retinoic acid (RAR) and triiodothyronine (TR) nuclear receptor mRNA in rat brain: effect of the administration of retinoids

International audienceAging is accompanied by troubles resulting from changes in hormonal and nutritional status. Therefore, the abundance of mRNA coding for triiodothyronine (TR) and retinoic acid (RA) nuclear receptors was studied in the brain of young, adult and aged (2.5, 6 and 24 months, respectively) rats. In the brain of aged rats, there was a lower abundance of TR and RAR mRNA and a lower activity of tissue transglutaminase (tTG), an enzyme the gene of which is a target for retinoids. Administration of RA in these rats restored TR and RAR mRNA and the activity of tTG in the brain. The importance of these observations to the function of the aged brain is discussed

Neuronal morphology and synaptic plasticity in the hippocampus of vitamin A deficient rats

Vitamin A (retinol) and related retinoids are micronutrients provided by food. Retinol derivatives are growth factors important for development, cell differentiation and tissue homeostasis, especially in the brain. Objective: The hippocampus is a pivotal brain structure for learning and memory and hippocampal-dependent memory is highly sensitive to retinoids action. However, the underlying mechanisms are still unclear. In this study, we characterized the impact of vitamin A deficiency on memory and neuronal plasticity, focusing on the CA1 region of the hippocampus in rats. Methods: Weaned male Wistar rats were fed a control (5 UI/g) or deficient vitamin A diet (0 UI/g) for 10 weeks. The effect of vitamin A supplementation (20 UI/g) for 3 weeks was also tested. Memory performances were assessed in the Y-maze (n = 24–30/group), retinoic acid levels were measured (LC-MS/MS) in the serum and in the hippocampus (n = 5/group), CA1 neuronal architecture was analyzed with Golgi staining (n = 17–20 neurons/group) and electrophysiological patch-clamp recordings were performed on hippocampal brain slices (n = 6–11/group). Results: Vitamin A deficiency from weaning significantly lowered hippocampal levels of retinoic acid, reduced dendritic length and branching of CA1 pyramidal neurons and decreased spontaneous glutamatergic synaptic events and synaptic plasticity. When replenishment with moderate dose of dietary vitamin A for 3 weeks was done, most of the synaptic and morphological alterations were absent. Conclusion: This study provides new mechanistic insight to understand the critical role of retinoic acid in hippocampal function

A mid-life vitamin A supplementation prevents age-related spatial memory deficits and hippocampal neurogenesis alterations through CRABP-I

Age-related memory decline including spatial reference memory is considered to begin at middle-age and coincides with reduced adult hippocampal neurogenesis. Moreover, a dysfunction of vitamin A hippocampal signalling pathway has been involved in the appearance of age-related memory deficits but also in adult hippocampal neurogenesis alterations. The present study aims at testing the hypothesis that a mid-life vitamin A supplementation would be a successful strategy to prevent age-related memory deficits. Thus, middle-aged Wistar rats were submitted to a vitamin A enriched diet and were tested 4 months later in a spatial memory task. In order to better understand the potential mechanisms mediating the effects of vitamin A supplementation on hippocampal functions, we studied different aspects of hippocampal adult neurogenesis and evaluated hippocampal CRABP-I expression, known to modulate differentiation processes. Here, we show that vitamin A supplementation from middle-age enhances spatial memory and improves the dendritic arborisation of newborn immature neurons probably resulting in a better survival and neuronal differentiation in aged rats. Moreover, our results suggest that hippocampal CRABP-I expression which controls the intracellular availability of retinoic acid (RA), may be an important regulator of neuronal differentiation processes in the aged hippocampus. Thus, vitamin A supplementation from middle-age could be a good strategy to maintain hippocampal plasticity and functions

Plasma retinol and association with socio-demographic and dietary characteristics of free-living older persons : the Bordeaux sample of the three-city study

International audienceThe objective was to describe retinol plasma concentration and its association with socio-demographic characteristics and dietary habits in French older persons. The study population consisted of 1664 subjects aged 65 + from Bordeaux (France), included in the Three-City cohort. Retinol plasma concentration was determined in fasting blood samples. Dietary assessment was performed by a food frequency questionnaire allowing estimation of weekly intake of dietary sources of vitamin A or provitamin A. The weekly number of glasses of alcohol was also recorded. Age, sex, marital status, educational and income levels, body-mass index (BMI), and smoking were registered. Cross-sectional analysis of the association between plasma retinol and socio-demographic characteristics and dietary habits was performed by multilinear regression. Mean plasma retinol was close to the homeostatically regulated concentration of 2.0 µmol/L but ranged from 0.35 to 6.77 µmol/L. It was higher in women and divorced or separated individuals, and increased with income but not with age or educational level. Plasma retinol was positively and independently associated with the frequency of offal consumption and to the number of glasses of alcohol consumed per week. These results allow targeting older individuals who are at risk of either excessive or deficient vitamin A status and who should benefit from dietary counseling

Experimental protocols.

<p>Weaning rats (3 weeks old) were submitted to 11 weeks or 14 weeks of vitamin A deficiency (VAD). The first two experiments were intended to study the effects of VAD and/or RA administration on hippocampal neurogenesis. The third experiment was designed to study the effects of VAD and/or RA administration on spatial memory and hippocampal neurotrophic receptor expression. The arrows and the grey bars indicate VAD and RA treatment, respectively.</p